receptors functions and signal transduction-...
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University of Jordan 1
Receptors Functions and Signal
Transduction- L3
Faisal I. Mohammed, MD, PhD
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Second Messenger Targets
Enzymes
Modulate phosphorylation
Phosphorylation activation or inactivation
Protein Kinases
Increase phosphorylation
Protein Phosphatases
activated by Ca2+/calmodulin
Decrease phosphorylation ~
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Second Messengers
Calcium (Ca2+)
Target: calmodulin
Calmodulin protein kinases B (calcium
calmodulin dependent protein kinase)
Cyclic nucleotides
cAMP & cGMP
Target: protein kinases ~
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Second Messengers
Diacylglycerol (DAG) & IP3
From membrane lipids
DAG Protein Kinase C (membrane)
IP3 Ca2+ (endoplasmic reticulum) ~
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Hormones That Use 2nd Messengers
Hormones cannot pass through plasma
membrane use 2nd messengers.
Catecholamine, polypeptide, and glycoprotein
hormones bind to receptor proteins on the target
plasma membrane.
Actions are mediated by 2nd messengers
(signal-transduction mechanisms).
Extracellular hormones are transduced into
intracellular 2nd messengers.
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Polypeptide or glycoprotein hormone binds to receptor protein causing dissociation of subunit of G-protein.
G-protein subunit binds to and activates adenylate cyclase.
ATP cAMP + PPi
cAMP attaches to inhibitory subunit of protein kinase.
Inhibitory subunit dissociates and activates protein kinase.
Adenylate Cyclase-cAMP
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Adenylate Cyclase-cAMP (continued)
Phosphorylates enzymes within the cell to produce hormone’s effects.
Modulates activity of enzymes present in the cell.
Alters metabolism of the cell.
cAMP inactivated by phosphodiesterase.
Hydrolyzes cAMP to inactive fragments.
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G-Protein-coupled Receptors
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Binding of Epinephrine to -adrenergic receptor in plasma membrane activates a G-protein intermediate, phospholipase C.
Phospholipase C splits phospholipid into inositol triphosphate (IP3) and diacyglycerol (DAG).
Both derivatives serve as 2nd messengers.
IP3 diffuses through cytoplasm to endoplasmic reticulum (ER).
Binding of IP3 to receptor protein in ER causes Ca2+ channels to open.
Phospholipase-C-Ca2+
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Phospholipase-C-Ca2+
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Phospholipase-C-
Ca2+
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Ca2+- Calmodulin (continued)
Ca2+ diffuses into the
cytoplasm.
Ca2+ binds to
calmodulin.
Calmodulin activates
specific protein kinase
enzymes.
Alters the
metabolism of the
cell, producing the
hormone’s effects.
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Ca2+- Calmodulin (continued)
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Neurotransmitter Release: exocytosis and endocytosis
1. Transmitter synthesized and stored
2. Action Potential
3. Depolarization: open voltage-gated Ca2+
channels
4. Ca2+ enter cell
5. Ca2+ causes vesicles to fuse with
membrane
6. Neurotransmitter released (exocytosis)
7. Neurotransmitter binds to postsynaptic
receptors
8. Opening or closing of postsynaptic
channels
9. Postsynaptic current excites or inhibits
postsynaptic potential to change
excitability of cell
10. Retrieval of vesicles from plasma
membrane (endocytosis)
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Transmitter Inactivation:
reuptake and enzymatic breakdown
Reuptake by transporters
Reuptake by
transporters
(glial cells)
Enzymatic
breakdown
Neurotransmitter can be recycled in presynaptic terminal
or can be broken down by enzymes within the cell
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Receptors are large, dynamic proteins that exist along and within the cell membrane.
Dynamic – they can increase in number and avidity for their neurotransmitter according to circumstances.
Two Types of Post synaptic Receptors:
Ionotropic receptors: NT binding results in direct opening of specific ion channels
Metabotropic receptors: binding of NT initiates a sequence of internal molecular events which in turn open specific ion channels
NT – Receptor Binding
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NT binding -> Membrane Potential
Response
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Ionotropic Receptors Work very fast; important role in
fast neurotransmission
1. Each is made of several
subunits (together form the
complete receptor)
2. At center of receptors is channel or pore to allow flow of ions
3. At rest - receptor channels are closed
4. When neurotransmitter binds -- channel immediately opens
5. When ligand leaves binding site -- channel quickly closes
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Metabotropic Receptors…
Work by activating other proteins called G proteins
1. Each is made of
several
transmembrane
regions
2. Stimulate or inhibit the opening of ion channels in the cell membrane
3. Work more slowly than ionotrophic receptors
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Metabotropic Receptors…
1. Stimulate or inhibit certain effector enzymes
2. Most effector enzymes controlled by G proteins are involved in synthesis of second messengers.
*First messenger: ligand.
*Second messenger:
effector enzyme
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Second messengers: Activate Protein Kinases
Can work by affecting:
NT production, no.
synapses formed,
sensitivity of receptors,
or expression of genes
(long term effects).
Can result in
amplification -
interconnections.
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Other Metabotropic Receptors
Work more slowly than ionotropic receptors
1. Though it takes longer for
postsynapic cell to respond,
response is somewhat longer-
lasting
2. Comprise a single protein subunit, winding back-and-forth through cell membrane seven times (transmembrane domains)
3. They do not possess a channel or pore
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PKC
Phosphorylates
many substrates,
can activate
kinase pathway,
gene regulation
PLC- signaling pathway
THANK YOU
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